Functional human IgA targets a conserved site on malaria sporozoites

Joshua Tan, Hyeseon Cho, Tossapol Pholcharee, Lais S. Pereira, Safiatou Doumbo, Didier Doumtabe, Barbara J. Flynn, Arne Schön, Sachie Kanatani, Samantha O. Aylor, David Oyen, Rachel Vistein, Lawrence Wang, Marlon Dillon, Jeff Skinner, Mary Peterson, Shanping Li, Azza H. Idris, Alvaro Molina-Cruz, Ming ZhaoLisa Renee Olano, Patricia J. Lee, Alison Roth, Photini Sinnis, Carolina Barillas-Mury, Kassoum Kayentao, Aissata Ongoiba, Joseph R. Francica, Boubacar Traore, Ian A. Wilson, Robert A. Seder, Peter D. Crompton

Research output: Contribution to journalArticlepeer-review

Abstract

Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.

Original languageEnglish (US)
Article numbereabg2344
JournalScience translational medicine
Volume13
Issue number599
DOIs
StatePublished - Jun 23 2021

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'Functional human IgA targets a conserved site on malaria sporozoites'. Together they form a unique fingerprint.

Cite this